19-halo androstenes



3,101,356 19-HALO ANDROSTENES Albert Bowers, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 12, 1962, Set. No.'201,799 Claims priority, application Mexico Mar. 13, 1962 23 Claims. (Cl. 260-397.4)

The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.

More particularly, the present invention relatesto novel 19+halo-A -androsten-17 3-ol-3-one derivatives.

The novel compounds of the present invention are represented by the following formulas:

In the above formulas R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen, lower alkyl, lower alkenyl or lower alkinyl; Z represents hydrogen, methyl, chlorine or fluorine, all having at or B configurations in Formula A; Y represents a double 'bond or a saturated linkage each between -1 and C-2; and X represents chlorine or fluorine. 1

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to SEQECS 5 carbon atoms, acyloxy containing up to 12 carbon atoms,

nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t butylacetate, phenoxyacetate, cyolopentylpropionate, aminoaceta-te, and [St-chloropropionate.

The compounds represented by the above formulas have anabolicandrogenic' properties, and inhibit the'pro-duction of pituitary gonadotrophic hormones and A.C.T.H. .In addition, they exhibit anti-estrogenic activity and lower the blood, liver and adrenal cholesterol levels. Further more, they are very useful in the control of fertility and psychotic conditions, and stimulate the appetite.

The novel compounds of the present invention are prepared by the process exemplified as follows:

lj Hr, 1

1 amuse Patented Aug. 20, 1963 v rC 0R I on 3' Lugs Inc an:

In the aboye tormulas R R X and Z have the same meaning as previously set forth; R represents hydrogen, lower alkyl or lower alkinyl; v

In practicing the process outlined above, the starting componnd'which is a Not-unsubstituted-17fi-acyloxy-19- halo-A -androsten-3/3-ol (I: R =acyl, R =H) is treated under conventional Oppenauer conditions tov produce the corresponding 17a-unsubstltuted-17/3-acyloxy-19-halo-A androsten-3-one"(II: R acyl, R =H) which upon conventional saponificat-ion with a base yields the correspond- (II: R =R =H). v

The Nor-substituted starting compounds [I: R =lower (alkyl or alkinyD] may have a 1713-free hydroXyLand when treated under conventional Oppenauer conditions, there is afforded the corresponding 17easubstituted-19-halo-A -am dr0sten 1'7,B-ol-3-0ne derivatives [Hz R =lower (alkyl or alkinyl) The A -3-ketones (11) upon reaction with ethylene gly- 17tat-unsubstituted-19-halo-A -androsten-17,8-01-3-one- 3 col,-in the presence of p-toluenesulfonic acid yield the corresponding 3 cycloethylenedioxy A androstene compounds (III) which upon treatment with an organic peracid, such as monoperphthalic acid, in a suitable solvent, e.-g. chloroform, give the corresponding 3-cycloethylenedi- OXY-19-ha10-50t,60t-OXldO derivatives (IV).

Upon reaction of the latter 3cycloethylenedioxy-Sm6aoxido compounds with methyl magnesium bromide in an inert solvent, such as ether or tetrahydrofuran, followed by conventional working up and treatment of the resulting residues with a mineral acid, such as 8% sulfuric acid, and thereafter with thionyl chloride in pyridine at about C. for approximately 4 minutes, there are obtained the corresponding 19halo-6,8-methyl-A -androsten-175-01- 3-one direvatives (V: Z=;8-methyl). These 6/3-methyl derivatives are converted into the corresponding Got-methyl derivatives (V: Z'=a-methyl) by treatment with an alkali metal hydroxide.

When treating the 3-cycloethylenedioxy-5a,6a-oxido compounds (IV) with anhydrous hydrogen chloride in a suitable'organ-ic solvent, e.g. ethyl acetate or acetic acid, there are produced the corresponding 6a-chloro-19-halo- A -androsten-17B-ol-3-one derivatives (V: Z=oc-Chi01l116).

Upon reaction of the 3cycloethylenedioxy-5u,6a-0xido compounds (IV) with anhydrous hydrogen fluoride, preferably in the presence of boron trifluoride etherate, followed by treatment with hydrogen chloride, there are produced the corresponding 6oa-fiuoro-19-halo-A -androsten-17B-ol-3-one derivatives (V: Z=a-fluorine).

The 19-halo-A -androsten-l7p-ol-3-one derivatives (II) are treated with ethyl orthotormate in the presence of p-- toluenesulfonic acid and in an inert solvent, thus afiording the corresponding -19-ha1o-3-ethoxy-A -androstadien- 17/3-01 derivatives, which upon reaction with approximately l rnolar equivalent of an N-chloro amide or imide, such as N-chloro succinimide in the presence of sodium acetate and acetic acid yield the corresponding 6B-chloro-19-halo- A -androsten-175-ol-3-one derivatives (V: Z=/8-chlorine).

The aforesaid 19halo-3-ethoxy-A -androstadiene-17p)- ol derivatives are treated with perchloryl fluoride in dimethyl tormamide to produce the corresponding 6 8-fluoro-19-halo-A 4androsten 17,8 o1 3 one derivatives (V: Z=B-liuorine) The l9-halm17u-alkinyl-n aandrosten l7fi ol 3 one compounds of the present invention (V: R =alkinyl) are converted into the corresponding 19- alo17a-alkenyl-A androsten-17B-ol-3-one derivatives (V: R alkenyl), by hydrogenation with approximately 1 molar equivalent of hydrogen, in pyridine solution in the presence of a suitable catalyst, such as 2% palladium on calcium carbonate at room temperature and under a pressure or about 1 atmosphere.

The 19-halo-A -androsten-17,8-ol-3 one compounds of the present invention (V) upon treatment with ethyl orthoformate in an inert solvent, e.g. dioxane, and in the presence of p-toluenesulfonic acid, furnish the corresponding 19-halo-3-ethoxy-A -androstadiene. derivatives, which are treated with approximately 1 molar equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the presence of a catalytic amount of acid and in an inert solvent to give the corresponding 19 halo-A fi-androstadien-1718- ol-3-one derivatives (VI).

When treating the 19-halo-A androsten-175-ol-3=one compounds (V) with 2,3-diohloro-5,6-dicyano-1,4 benzoquinone in an inert solvent such as diox-ane, prefierably at reflux temperature, for a period of time of about 10 hours, there are produced the corresponding 19-halo-A -androstadien-17,8ol-3-on-e compounds (VII).

The aforesaid A androstadiene compounds (VI) are converted into the corresponding A -androstatriene derivatives by fiurther treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, under the same conditions as specified hereinbetore, tor the production of the A -derivatives (VI).

The compounds of the present invention hla-v' g a seci ondary hydroxyl, namely the 17u-unsubstituted-17B-alcohols are conventionally acylated in pyridine with an acylating agent, such as an anhydride or an acyl chloride derived from hydrocarbon oarboxylic acids of the previously defined type, to produce the corresponding acylates.

The compounds of the present invention having a tertiary hydroxyl present in the molecule, i.e. the 17u-substituted-17Bealcohols, are conventionally esterified, in the presence 0t p-toluenesulfonic acid with an acylating agent such as acetic anhydride or caproic anhydride, thus ado-rd ing the corresponding esters.

The following specific examples serve to illustrate, but are not intended to restrict the scope of the present invention.

PREPARATION 1 2 cc. of dihydropyrane were added to a solution of 1 1g. of 19-iiuoro-n androsten-3,6-ol-17-one (obtained in accordance with my copending U.S. patent application Serial No. 201,803, tiled of even date, by treating N androstene-3fl-19 diol-l7-one 3 acetate disclosed in my US. Patent No. 3,065,228, with an a-fluorinated amine or with tosyl chloride followed by reaction with an alkali metal fluoride and turther conventional saponification of the ester group) in 15 cc. of benzene and about 1 cc. was distilled to remove moisture. 0.4 g. of p-toluenesul fonic acid were added to the cooled solution, which was then allowed to stand at room temperature tor 4 days. The

solution was washed with sodium carbonate and water,

dried and evaporated. The residue was chromatographed on 15 g. of neutral alumina. Crystallization of the tractions eluted with hexane from pentane yielded the 3-tetrahydropyranylether of 19-fluoro-A -androsten-3 5- ol-17-one. A solution of 1 g. of sodium borohydride in 3 cc. of water was added to an ice-cooled solution of 1 g. of the latter product in 120 cc. of methanol and the mixture was allowed to stand for 6 hours at room temperature. The excess reagent was decomposed by addition of acetic acid, the solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract was washed with water, dried and evaporated. The solid residue was purified by crystallization from acetone-hexane to give the 3-tetnahydropyranylet-her of 19'-fluoro-A -androstene-3,8,17fi-diol.

A mixture of the latter compound, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the B-tetrahydropyranlyether-17 acetate of 19-fluoro-A -androstene-3p,l7fi-diol. A solution of 500 mg. of the last-named steroid in 25 cc. of acetone was treated with 1 cc. of concentrated hydrochloric acid and the mixture kept at room temperature overnight. It was then poured into water, extracted with methylene chloride and the organic extract washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone hexane gave the 17-acetate of l9-fluoro-A -androstene- 3,8,175-diol.

19-chloro-A -androsten-3,B-ol-17-one (obtained in accordance with the aforesaid patent application) was treated fol-lowing the above procedures, thus affording the 17-acetate of '19-chloro-A -androstene-3,B,17fi-diol.

Example I A solution of 1 g. of the 17-acetate of 19-fluoro-A androstene-3p,17,8-diol in cc. of toluene and 20 cc. of cyclohexanone was dried by distilling off 10 cc. of the solvent. A solution of 1 g. of aluminum isopropoxide dissolved in 7 cc. of anhydrous toluene was then added and the mixture was refluxed for 20 minutes; 4 cc. of acetic acid were added and the solvents removed by steam distillation. The product was extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, water, 10% sodium car- A suspension of 1 g. of the acetate of l9-fluoro-A -androsten-17/3-ol-3-one (Compound N0. 1) in 60 cc. of methanol was treated with a solution of 1 g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with water. The for-med precipitate was collected and recrystallized from acetone-hexane to yield 19-fluoro-A androsten-l7/3-ol-3-one (Compound No. 3).

The acetate of l9-chloro-A -androsten-l7 3-ol-3-one (Compound No. 2) was treated in accordance with the above procedure, thus affording 19-chloro-A -androsten- 17,B-ol-3-one (Compound No. 4).

The compounds listed under A (obtained in accordance with the aforesaid patent application) were treated according to Example I, thus affording the corresponding compounds set forth under B.

Example III A mixture of 5 g. of l9-fluoro-A -androsten-175-01-3- one (Compound No. 3), 15 cc. of anhydrous benzene, 60 cc. of et-hyleneglycol distilled over sodium hydroxide and 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3-cycloethylenedioxyl9-fiuoro-A -androsten-175-01 (Compound No. 9).

Following the same procedure, there were treated the Compound Nos. 4 to 8, inclusive, thus affording respectively:

Compound No.2

( l0) 3 cycloethylenedioxy- 19-chloro-A -androstenl 1 3-cycloethylenedioxy-l9-fluoro-17a-methyl-A =androsten-17B-ol (12) 3-cycloethy1enedioxy-19-chloro-l7a-methyl-A 'androsten- 1 718-01 (13) 3-cycloethylenedioxy-19-fluoro-17a-ethiuyl-A androsten-17B-ol (14) 3-cyoloethylenedioxy-19-chloro-17a-ethinyl-A androstenl7fi-ol Example IV A solution of 2.5 g. of 3-cycloethylenedioxy-l9-fluoro- A -androsten-17fi-ol (Compound No. 9) in 100. cc. of chloroform was cooled to 0 C. and mixed with Ll molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours,

minutes.

diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetoneahexane gave 3-cycloethylenedioxy-19-fluoro-5a, 6a-oxido androstan-l7fl-ol (Compound No. 15).

The Compounds Nos. 10 to 14, inclusive, were treated following the above procedure, thus furnishing respectively:

Compound No:

16) 3-cycloethylenedioxy-l9-chloro-5a,6a-oxido-'an- =drostan-l7fl-ol 17 3-cycloethylenedioxy-19-fluoro-17a-methyl-5a,

6e=oxido-and-rostan-l7p-ol 18 3-cycloethylenedioxy-l9-chlorol7a-methyl-5u,

6m-oxido-androstan-l7fi-ol 19 3-cycloethylenedioxy-19-fiuoro-17a-ethinyl-5a,

Got-OXldO-fll'ldl'OStflIl-1713-01 (20) 3-cycloethylenedioxy-19-chloro-l7a-ethinyl-5a,

6a-oxido-androstan-l7fl-ol Example V To a solution of 20 cc. of 4 N methylmagnesium bromide in ether was added, with stirring, a solution of 1 g. of 3-oycloethylenedioxy-l9-fluoro-5a,6a-oxido-androstan 17ct-ol (Compound No. 15) in 3 0 cc. of dry tetrahydro- -furan and the stirred mixture heated under reflux for 30 The condenser was then replaced by a calcium chloride tube, the ether allowed to boil 0E and when the vinternal temperature reached 54 C., the condenser was readapted and the mixture refluxed for an additional 4 hours. 200 'cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer to a separatory funnel. It was diluted with ethyl acetate, the organic layer was separated, dried and evaporated to dryness, thus aflording a solid residue.

A solution of the above residue in 70 cc. of methanol and 7 cc. of 8% aqueous sulfuric acid was refluxed for 40 minutes. It was then neutralized with saturated sodiurn carbonate solution, concentrated to ca. 20 cc. in vacuo and poured into water. The formed precipitate was filtered off, washed thoroughly with Water and air dried.

A solution of the dry precipitate in 7 'cc. of dry pyridine was cooled to 10 C, treated with 0.4 cc. of 'thionyl chloride and the mixture allowed to stand for 4 minutes at this temperature. Ice-water was added and the crystalline precipitate was filtered, washed and dried, yielding l9 fluoro 6,8-rnethy-l-M androsten-17B-ol-3-one (CompoundNo. 21). I

The Compounds Nos. 16 to' 20, inclusive, were treated by the above procedure, thus furnishing respectively:

Compound =No.

(22) 19-chloro-6 8-n1ethyl-A -androstenl 7B-ol-3-one (23 19-luoro-6fi,17a-dimethyl-A androsten--01- 3-one (24) l9 chloro-6 3,17a-dimethyl-A -androsten-175-01- 3-one (25) l9-fluoro-6ft-methyl-17u-ethinyl-A -androsten- 17,8-ol-3-one (26) l9-chloro-6,8-methyl-17a-ethinyl-A -androsten- 17fl-ol-3-one Example VI 1 g. of 19-fiuoro-6,8methyl-A aan-drosten-17B-ol-3-one (Compound No. 2 1) was dissolved in 20 cc. of methanol containing 0.2 g. of sodium hydroxide and the mixture was kept tor one and a half hours at room temperature, then poured into water and extracted with methylene chloride. Evaporation of the methylene chloride solution and crystallization of the residue from acetone hexane,

yielded 19-fiuoro 60c -methyl-A -androsten-l718-ol-3-one (Compound No. 27).

Following the same procedure, the Compounds Nos. 22 to 26, inclusive, were converted respectively into:

Compound No.:

(28) 19chloro-6a1tnethyl-A -androsten-17B-ol-3-one (29) 19-fiuoro-6u,17adimcthyl-A -androsten-1713-01- 3-one (30) 19-chloro-6u,17a-dimethyl-A' -androsten-l75-01- 3-one (31) 19 fluoro-6wrnethyl-17a-ethinyl-A -androsten- 17/3-ol-3-one (3-2) 19 chloro-6ct-rnethyld7u-ethinyl-M-androsten- 17 3-ol-3-one Example VII Into a suspension of 1 g. of 3-cyc1oethylenedioxy-19- iluoro-Sa,6a-oxido-androstanl76-01 (Compound No. 15) in 35 cc. of glacial acetic acid, was passed a slow stream of dry "hydrochloric acid; after minutes all the solid material was dissolved. The gas was passed through the reaction mixture .for a total of 5 hours. The solution was concentrated to about one-third its initial volume by distillation under reduced pressure at 35 C., then it was poured into ice-water. The precipitate formed was collected, washed with Water to neutrality and dried. Recrystallization from methylene chloride afiorded Goa-011101 049- fluoro-Mandrosten-17fi-ol-3-one (Compound No. 33).

The Compounds Nos. 16 to 20, inclusive, were treated by the above procedure, thus yielding correspondingly:

Compound No.:

(34) 6a,19-dichloro-A -androsten-175-01-3-one (35) 6a-chloro 19 fluoro-l7a-methyl-A -androsten- 175-.ol-3-one (3 6) 6a, 19-dichloro-17a-methyl-A -androsten-1718-01- 3-one (37) 6u-chloro 19- fluoro-lMethinyl-N-androsten- 17,8 ol-3-0ne (38) 6a,19-dichloro-17a-ethinyl-A -androsten-17p-ol 3-onc Example VIII 2.8 cc. of boron trifiuoride etherate was slowly added with stirring to 220 mg. of anhydrous hydrogen fluoride cooled in an acetone-Dry Ice bath.

To a solution of 1 g. of Compound No. in 10 cc. of a mixture of equal parts of benzene and ether was added 1.3 cc. of the fluoroboric acid reagent. The mixture was kept for 3 hours at room temperature, then washed four times with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was dissolved in 50 cc. of ethyl acetate and there was added 1 cc. of concentrated hydrochloric acid. The resulting mixture was kept at room temperature for 5 hours, then it was 'washed abundantly with water. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from acetone-hexane yielded 6m,19-difiuoro-A -androsten- 17 8-01-3- one (Compound No. 39).

The Compounds Nos. 16 to 20, inclusive, were treated by the above procedure, thus aifording respectively:

3-one (Compound No. 3) in 7.5 cc. of anhydrous peroxidefree diox-ane was treated with 1.2 cc. of freshly distilled ethyl orthotormate and 0.8 g. of p-toluenesulfonic acid. The mixture was stirred at room temperature for 15 minutes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water Washed and dried. Recrystallization from acetonehexane afforded 3-ethoxy-19-fluoro-A andnostadiend7B- ol (Compound No. 45).

The Compounds Nos. 4 to 8, inclusive, were treated by the same procedure, thus ifurnishing respectively:

Compound No.:

(46) 3-ethoxy 19-chlom-A -androstadien-173-01 (47 S-ethoxy 19 fluoro-17a-n1ethyl-A -androstadien-l7,8-ol 48) S-ethoxy 19 chloro-l7a-methyl-A -androsta- (49) 3-ethoxy 19 fluoro-17a ethinyl-A -androstadien-17fi-ol (50) 3-ebhoxy 19 chloro-17a-ethinyl-A -androstadien-17fi-0l Example X A mixture of 5 g. of '3-ethoxy-l9-fluoro-A aandrostadien-17fi-ol (Compound No. 45), 2 g. of anhydrous sodium acetate and cc. of acetone, was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C. for 30 minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with Water, dried under vacuum and recrystallized from acetone thus giving 6fl-chloro-19-fluoro-A .androsten-17fi-ol-3-one (Compound No. 51).

The Compounds Nos. 46 to 50, inclusive, were treated by the above procedure, thus yielding correspondingly:

Compound No.:

(52) 6B,19-dicMoro-A -androsten-17B-o1-3-one 5 3) 6B-chl0ro 19- fluoro-17oc-methyl-A -androsten- 1 g. of 3 ethoxy 19 fiuoro-A -androstadien'-17 3-01 (Compound No. 45) was dissolved in 25 cc. of dimethylformamide. The solution was cooled to 0 C. and a stream of perchloryl fluoride was passed for 5 minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. By chromatography over washed alumina there was obtained 6/3,19-difiuor0-A -and1'osten-17B-oi-3-one (Compound No. 57).

Upon treatment of Compounds Nos. 46 to 50, inclusive, by the same procedure, there were respectively produced:

Compound No.:

(58) 6B-fluoro-19-chloro-A -androsten-17,8-ol-3-one (59) 6B,19-difluoro-17a-methyl-A -andr0sten-17 3- 0l-3-one (60) 6/3-fiuoro-g19-chloro17a-methyl-A -androsten! 17B-o1-3-one (61) 6,8,19-difluoro-17a-ethinyl-A -androsten-- (62) 6B-fluoro-19-chloro-17a-ethiny1-A -androsten- 17 3-ol-3-one 9 Example XII A solution of 1 g. of 19-fiuoro-17a-ethinyl-M-3udrostenl7B-ol-3-one (Compound No. 7) in 40* cc. of pwlidine was hydrogenated at 25 C. and 570 mm. in the presence of 400 mg. of pre-hydrogenated 2% palladium calcium carbonate catalyst. 1

When 1.1 molar equivalents of hydrogen had been absorbed, the reaction was stopped, the catalyst separated by filtration through celite, Washed with ethyl acetate and the combined solutions evaporated to dryness in vacuo,

Compound No:

(64) 19-chloro-17m-vinyl-A -androsten-17,8-01-3-one (65) 19-fluoro-6fi-methyl-l7u-vinyl-A -androsten- (73) 6,8-chloro-19-fiuoro-17a-vinyl-A -androsten- 17 8-ol-3-one (74) 65,19-dichloro-17a-vinyl-A -androsten-175-01- 3-one (75) 66,19-diHuoro-17a-vinyl-A -androsten-17,8-01- 3-one (76) 6/3-i'luoro-19-chloro-l7qa-vinyl-A -androsten- 17fi-ol'3-one Example XIII A suspension of 1 g. of 19-fiuoro-A -androsten-175-013- one (Compound No. 3) in 7.5 cc. of anhydrous peroxidefree dioxane was treated with 1.2 cc. of freshly distilled ethyl orthoformat-e and 0.8 g. of p-toluenesulfonic acid.

The mixture was stirred at room temperature for 15 min utes and the resulting solution let stand for 30 minutes further. 0.8 cc. of pyridine were added and then water. The formed precipitate was collected by filtration, water washed and air dried. Recrystallization from acetonehexane afforded 3-ethoxy-19-fiuoro-A -androstadien l7pol, identical with Compound No. 45 obtained in Example IX.

A solution of 1 g. of the latter compound in 20 cc. of tetrahydrofuran was cooled to O'C. and there were added 1.05 molar equivalents of 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone and 100 mg. of p-toluenesulfonic acid. The resulting mixture was further stirred at C. for 30 minutes. The precipitated 2,3-dichloro-5,6-dicyano-hydroquinone was filtered oiland 100 cc. of methylene chloride were added to the filtrate.

Theorganic solution was washed with aqueous sodium hydroxide solution until the washings were colorless, thenwith water to neutrality, dried over anhydrous.

sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 19-fiuoro-A -androstadien- 17 8-ol-3-one (Compound No. 77),

ll) The Compounds Nos. 4 to 8, inclusive, were treated following the same procedure, thus yielding respectively:

Compound No:

(78) ;19-ch1oro-A -androstadien-17,8-01-3-one 5 (79) v19-fluoro-17m-methy1-A -androstadien-175- ol-3-one (80) 19-ch1oro-17oc-methyl-A -androstadien-17 ol-3-one (81) 19-fluoro-17ot-ethinyl-A -androstadien-17,8-

ol-3-one (82) 19-chloro-17a-ethinyl-A -androstadien-17 3- ol-3-one Example XIV The Compounds Nos. 21 to 26, inclusive, were treated in accordance with the preceding example, thus atfording res pe otively Compound No.: I

(83) 19-fluoro-6 methyl-M androstadiem17 8-01-3- one 1 (84) 19-chioro 6-n1ethy1-A -androstadien-175-01-3- one i (85) 19-fiuoro-6,17oa-dim'ethyl-A -androstadien-17B- o1-3-one (86) 19 chloro- 6,1704 dimethyl-A 'andmstadieu- 87) 19-fluoro-6 methyl-17a ethinyl-A -androstadien-17B-ol-3-one (88) 19-chloro-6 methyl-17a ethinyl-A -androstadien-17/3-ol-3-one Example XV Compound No.:

(89) 6-ch1oro- 19 fluoro-A -androstadien-175-01-3- one (90) 6,19-dichloro-A -andnostadien-17fi-ol-3one (91) 6-chloro 19 fluo'ro-l7a-methy1-A -aridrostadien- 17B-ol-3-one (92) 6,19 -dich1oro 17a methyl-A -androstadien- 17,8-ol-3-one (93) 6-chloro-19 fiuor o-17a ethinyl-A -androsbadien-17flo1-3-one (94) 6,19 dichloro 17cc ethiny1-A -androstadien- 17,6-ol 3one (95 6,19-difluoro-A androstadien-17/3-ol-3-one (96) 6-fluoro-19 chloro-A -androstadien-175-01-3- one (97) 6,19-difiuorol7u-methyl-A -audrostadienl7,8-

ol-3-one (98) 6-fluoro 19 chloro-l7a-methy1-A -androsta- I dien-17B-ol-3-one (99) 6,19-difluoro-17 wethiny1-A -androstadien-17,8-

, ol-3-one (100) 6-fiuoro-19-chloro l7a-etthinyl-A -androsta- (lleH-17fi-0lw3-OI16 1 Example XVI The Compounds Nos. 63 and 64 were treated according to Example Xlll, thus furnishing respectively:' 19- fluoro-17a-vinyl A iandrostadien-17B-ol-3-one (Com- 65 pound No. 101).

Example XVII A mixture of 500 mg. of 19-fluor'io-A -androsten-1713-0 3-one (Compound No. 3), 10 cc. of dioxane and 350 mg.

of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was refluxed for 10 hours, It was then cooled, the 2,3diohloro-5,6-dicyano-1,44benzohydroquinone formed during the reaction filtered off, and the filtnate evaporated to dryness. The residue was dissolved in acetone and filtered through 10 g. of alumina. Crystallization from acetone-hexane gave 19-fluoro-A -:androstadien-17,8-01-3- one (Compound No. 103).

The Compounds Nos. 4 to 8, inclusive, were treated in accordance with the above procedure, thus furnishing respectively:

Compound N0.:

( 104) 19-ch1oro-A -androstadien-17 ,9-01-3-one 105) 19-fluoro-17a-methyl-A -androstadien-l 7,8-01- 3- one (106) 19-chloro 17otmethyl-A androstadien-17,8-

ol-3-one 107) 19-fluoro- 17a-ethiny1-A -androstadien- 17 8-01- 3-one (108) 19-chloro 17a-ethinyl-A -androstadien-17B- ol-3-one Example XVIIB The Compounds Nos. 21 to 32, inclusive, were treated in accordance with the preceding example, thus affording respectively:

Compound N0.:

( 109 19-fluoro-68-methy1-A "*aandrostadien-17,6-01-3- one 1 10) 19-chloro-6,8-methylA androstadien-17,8-01- 3-one 1 1 1 19-fluoro-6fl, 17cc dimethyl-A -androstadien- I (112) 19-ch1oro-6B, 17 oz dimethyl-A -androstadien- 17,B-o13-one 1 13) 19-fluoro-6B-methyl-17a-ethinyl-A -androsta dien-17,8-ol-3-one 1 14) 19-.chloro-6[3 methyl-17a-ethinyl-A -androsta- =dien-175aol-3-one 1 15 19-fluoro-6a-methyl-A -androstadien- 17 8-01- 3-one 1'16) 19'-ch1oro-6 wrnethyl-A 4androstadien-17B-ol- 3-one 1 17) 19-fluoro 6oz,17a-dimethyl-A -androstadien- 17/3-o1-3-one 1 18) 19-chloro 6a,17x-dimethyl-A -androstadienl7fl-ol-3-one 1 19) 19-fluoro-6a-methyl-17a-ethinyl-A -androstadien-17fl-ol-3-one (120) 19-chloro-6a-methyl-17a-ethinyl-A -androstadien-17;8-ol-3-one Example XIX Upon treatment of Compounds Nos. 33 to 44, inclusive, by the procedure of Example XVII, there were respectively produced:

1.2 Example XX The Compounds Nos. 63 and 64 were treated according to Example XVII, thus furnishing respectively: 19- tfluoro-l7a-vinyl-A -androstadien 17B ol-3-one (Compound No. 133) and 19-ohloro-17u-viny1-A -androstadien-17 3-ol-3 one (Compound No. 134).

Example XXI The Compounds Nos. 77 to 88, inclusive, upon treatment by the procedure of Example XVII, afforded respectively:

Compound No.2

1( 135 l9-fiuoro-A -androstatrien- 17B-o1-3-one 13 6) 19-chloro-A -androstatrien-17,8-01-3 -one 137) 19-fluoro-17a-methyl-A -androstatrien- 17fl-ol-3-one 13 8) 19-chloro-17u-methyl-A -androstatrienl7fl-ol-3-one 140) 19-ch1orol7oc-eflhinyl-A -androstatrien- 17 8-01-3 -one 141 19-fluoro-6-methyl-A -androstatrien- 17fi-ol-3-one 142) 19-chloro-6-methyl-A -androstatrien- 1718-01-3 -one (143) 19-fluoro-6,-17a-dimethyl-A -androstatrienl7 8-ol-3-one 144) 19-chloro-6,17a-methy1-A -androstatrien- 17fl-ol3-one 145) 19-fluoro-6-met-hyl-17a-ethiny1-A -androstatrien-17B-ol-3-one 146) 19-chloro-6-methyl-17ot-ethinyl-A -androstatrien-17,8:ol-3-one Example XXII The Compounds Nos. 101 and 102 of Example XVI were treated in accondance with Example XVII, thus yielding respectively: 19 fluoro 17oz vinyl-A -androstatrien 17,3 o1 3 one (Compound No. 147) and 19- chloro-17a-vinyl-All -androstratrien-l7fl-ol-3-one (Compound No. 148).

Example XXIII 'Ihe Compounds Nos. 65 to 76, inclusive, were treated in accordance with Example XIII, thus affording the corresponding A' -pre gnadiene derivatives.

Example XXIV A mixture of 1 .g. of 19fluoro-6,8-methyl-A -androsten- 17,6-ol-3-one (Compound N0. 21), 4 cc. of pyridine and 2 cc. of propiom'c anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization :Erom acetone-hexane gave 19 -fiuoro-6 8methyl- A -androste-n-17fl-ol 3 one propionate (Compound No. 149).

Upon esterification of Compounds Nos. 22, 27, 28, 33, 34, 39, 40, 51, 52, 57, 58, 77, 78, 83, 89, 95, 103, 109, 121 and 135 by the above procedure, there were respectively obtained:

Compound N0.: 7

( 150) 19-ohlouo-6 8-methyl-A -androsten--01- 3-one propionate 151) 19-fiuo1io-6a-methyl-A -androsten-175-01- 3-one propionate (152) 19-chloro-6a-methyl-A -androsten-1713-01- 3-0ne propionate 153) 605-0111010-19-fllIOI'O-A *aI1dTOStI1-'17131)].-

3-one propionate (154) 6a,19-dich1oro-A -androsten-17 3-o1-3-one propionate 13 (155) 6a,19-difluoro-A -androsten-17 8aol-3-one propionate (156;) Got-fluoro-19-chloro-A -andnoslten-175-01- 3 -one propionate (157) 6,8-chloro-19-fluoroA -androsten-171%01- 3-one propionate "(158) 6,8, 19-dichloro-A -androsten-1 7,8-01-3-one propionate (159) 6,8, 19-difluoro-A -androsten-17,8-01-3-0ne propionate v (160) 6,8-fluoro-19-ch1ono-A -androstcn-17/8 o1-,

3-one propionate 161) 19-fluoro-A -an-drostardien-175-.01-3-one propionate I Y 162) 19-chl-oro-A -androsta'dien-17fi-ol-3 one propionate 163) 19-fluor0-6-methyl A -androstadien-17;5'-ol- 3-one propionate 164) 6-ohloro-19-fiuoro-A -androstadien-17/3 ol- 3-one propionate Y 165 6,19adifluor-A -androstadien-176ml 3-one propionate 166) 19-fluoro-A -androstadien- 17,6-ol-3-one pnopionate (167) 19411101 0-6fl-methyl-A -androstadien-17,B-ol- 3-one propionate 168) 6a-chloro-l9-fiuoro-A -androstadien- 17,8-01- 3-one vpropionate I (169) 19-fluoro-A -androstatrien-17fi o1-3-one propionate Example XXIV-A The starting compounds of the preceding example were treated in accordance with that example, except that propionic anhydride was substituted by caproic arr-hydride, undecenoic anhydrilde and cyclopentyl propionic anhyldride, thus afiording respectively the corresponding caproates, undecenoates and cyclopentyl propionat'es of said starting compounds.

Example XXV To a solution of g. of '19-fluo=ro-17tr-rnethyl-A androsten-17fi-ol-3-one (Compound No. 5) in 100 cc. of anhydrous benzene there were added 1 g. or p-toluenesulfonic acid and cc. of caproic anhydride and the mixture was allowed to stand [for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the 16XOSS anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and-water. Drying, evaporation and crystallization of the residue from etherhexane produced l9-fluoro-l7a-methyl-A -androsten-175- ol-3-one caproate (Compound No. 170). I

Following exactly the same procedure, there were treated the Compounds Nos. 6, 7, 8, 29, 37, 42, 67, 72, 79, 87, 94, 106, 119, 134 137 140 and 147 thus furnishing respectively:

Compound No.:

(171) 19-chloro-17u-methy1-A -androsten-17;3-0l- 3-one caproate v (172) 19-fiuoro-17a-ethinyl-M-androstend7,8-01- 3-one caproate (173) 19-cl1lor0-17a-ethinyl-A -androsten-176-01- 3-one caproate (174) l9-fluoro-6et,17a-dimethy1-A -androsten-17 3 ol-3-one caproate 175) 6a-chloro-19-fluoro-17a-ethinyl-A -androsten l7fi-ole3-one caproate (176) 6u-fluoro-19-chl0ro-17a-methyl-A -androsten- 17,8-ol-3-0ne caproate (177) l9- fiuoro-6ot-methy1-17a-viny1-A -androsten- 17B-o1-3-one caproate (178) 6a-fluoro 19-ch1oro-17a-vinyl-A -androsten 17fl-ol-3-one caproate (179) 19-fluoro-17zx-methyl-A -androstadien- 17B- ol-3-one-caproate 180) 19fluoro-6-methyl-17a-ethiny1-A -androstadien-17/i-ol-3-one caproate 181) 6, l9-dichloro-17wethinyl-M -androstadien- 17/3-ol-3-one oaproate (182) 19-chloro-17a-methyl-A -androstadien-17/3- o1-3-0ne caproate stadien-17fi-ol-3-one caproate 184) 19-ch1oro-17tt-vinyl-A -androstadien-17pol-3-one caproate :(185) 19-fluor0-l7a-methy1-A -androstatrien- 17/8-ol-3-one caproate (186) 19-chloro-17u-ethiny1-A -androstatrien- 17fi-0l-3-one caproate 187) 19-fluoro-17a-vinylA androstatrien-176- ol-3-one caproate Example XXVI The starting compounds of the preceding example were treated in'laccordance with that example, except that caprioc anhydride was substituted by acetic anhydride, propionic anhydride and enanthic anhydride, thus furnishing respectively the corresponding acetates, propionates and enanthates of said starting compounds.

I claim: l. A compound of the following formula:

Z is selected from the group consisting of hydrogen,

a-methyl, fi-methyl, a-chlorine, fi-chlorine, a-fluorine and fi-fluorine; Y is a member of the group consisting of a double bond and a saturated linkage between 0-1 and 0-2; and X is selected from the group consisting of 1111- I orine and chlorine.

. 19-fluoro-A -androsten-17B-ol-3-one. 19-chloro-A -androsten-17,8-ol-3-one. 19-fluoro-17a-vinyl-n aandrosten-17/3-ol-3-one.

l9-chloro-17u-vinyl-A -androsten-17fi-ol-3-one. 19-chloro-17u-methyl-A -androsten-17/3-ol-3-one. 19-fiuoro-17o4-ethinyl-A -andr0sten-17 8-ol-3-one. 19-chlor0-17or-ethinyl-A -androsten-175-0l-3one. 19 fiuoro 6a,17a dimethyl A androsten 17f ol-3-one.

10. 6a chloro 19 fluoro 17a ethinyl A androsten-17B-ol-3-one. 1

, 11. 60 fiuoro 19 chloro 170a methyl A andros ten-17/8-ol-3-one.

12. 19 fluoro 6oz methyl 17cc vinyl A androsten17/8-ol-3-0ne. I

13. 6o: fiuoro 19 chloro 17oz vinyl A androsten-17,6-ol-3-one.

14. 19 chloro 17oz methyl A androstadien- 17 3-o1-3-one.

15,. 19 fluoro 6:! methyl 17a ethinyl A androstadien-1718-ol-3-one.

16. 19 chloro 17cc vinyl A androstadien 17p?- 'ol-3-one.

17. A compound of the following formula:

f H2O sisting of a double bond and a saturated linkage between C-1 and C-2; and X is selected from the group consisting of fluorine and chlorine.

18. 19 fluoro 17cc methyl A androstadien 17B- ol-3-one.

19. 19 fluoro 6 methyl 17a ethinyl A androstadien-17B-ol-3-one. I

20. 6,19 dichloro 17cc ethinyl A androstadienl7 8-0l-3-one.

21. 19 fluoro 17oz methyl A androstatrienl7fi-ol-3-one.

22. 19 chloro 17oz ethinyl A androstatrienl7B-ol-3-one.

23. 19 fluoro 17a vinyl A1316 androst'atrien 1713- ol-3-one.

References Cited in the file of this patent Mills et al.: Chem. and 1nd, June 24, 1961, page 946. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 